Say hello to the biggest little thing in biotechnology!
If you're a biologist, you know this molecule. Even if you're not, chances are good that you've seen a news article about the little beastie. This protein/RNA complex jumped into the scientific consciousness only a few years ago, but in this short amount of time it has already caused a global revolution in biotechnology, and I have a feeling we're only beginning to see what it's capable of. The little guy you see above is called Cas9, and it is changing the world as you read this.
In order to explain how Cas9 works, we need to know where it comes from. I can't recount the entire history of our molecule here, but Dr. Eric Lander has written an excellent article that ties together over 20 years of research that led up to where we are now . If you're interested in microbes, biotech, scientific mysteries or yogurt, I highly recommend giving it a read.
In a nutshell, our protein is part of an immune system for microbes. Bacteria and archea carry bits of DNA that came to be called "Clustered Regularly Interspaced Short Palindromic Repeats", or CRISPR for short. CRISPR loci were discovered by Dr. Francisco Mojica, who obsessed over the mysterious repetitive sequences for about a decade before realizing that they work sort of like a card catalog, recording sequences of viruses that infect the bacterium . Over the next few years, CRISPR caught the attention of a handful of labs who wanted to sort out how bacteria used them to ward off infection. This led to the naming of the CRISPR-associated (Cas) proteins, including our protein, Cas9. It soon became apparent that microbes could load the stored sequences into this protein, using them as guides to recognize viral DNA and slice it in two . But the DNA that Cas9 slices doesn't need to be viral DNA, and some ideas began to brew...
It is hard to say exactly who had the idea first--I'll leave that decision up to the patent lawyers--but the thought of using Cas9 to edit genomes bubbled quietly for a couple of years before a flurry of papers were published in 2012 and early 2013. Drs. Jennifer Doudna and Emmanuelle Charpentier worked together to publish a demonstration that Cas9 could use a customizable "guide RNA" to seek out and slice up practically any stretch of DNA you wanted to edit . At the same time, Dr. Feng Zhang's lab was working hard to prove that Cas9 could be used to make specific changes to the genomes of mouse and human cells . After this the floodgates opened, and labs around the world scrambled to get their hands on CRISPR/Cas9 as a means of quick and simple genome engineering in fish, frogs, corn, dogs, yeast, moss... and of course, humans.
It's still too early to say what impact Cas9 gene editing will have on our planet, but governments and ethics committees are in fierce debate right now over what (if anything) should be considered off-limits for CRISPR. These decisions could have a big impact on biomedical research, crop production, and even global ecosystems. For example, a proof-of-concept was published in October of a "gene drive" that uses Cas9 to spread anti-malaria genes through mosquito populations, potentially eradicating the disease worldwide . Nobody can know the future, but there is no question that Cas9 has a place in it.
This 3D model was adapted from the crystal structure of a Cas9 protein from the bacterium Staphylococcus aureus . While many other CRISPR/Cas structures exist, I chose this one simply because it has the fewest missing pieces. It contains a guide RNA molecule in complex with its targeted DNA. Notice the 180-degree twist of the DNA strand where it is pried apart by the Phosphate Lock Loop. The nucleotide complex is attached to this model by two sprues in the PAM motif of the DNA, and you can clip these if you want to separate the two. Or if you are interested in just the nucleotides, I have both a mini and mega model of the RNA/DNA complex by itself. This model is also available in either mini or mega.
Sources for the curious:
* Eric S. Lander, "The Heroes of CRISPR." Cell (2016)
 Francisco J. Mojica et al., "Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements." Journal of Molecular Evolution (2005)
 Josiane E. Garneau et al., "The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA." Nature (2010)
 Martin Jinek et al., "A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity." Science (2012)
 Le Cong et al., "Multiplex Genome Engineering Using CRISPR/Cas Systems." Science (2013)
* Valentino M. Gantz et al., "Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi." PNAS (2015)
 Hiroshi Nishimasu et al., "Crystal structure of Staphylococus aureus Cas9." Cell (2015)
*Free full text available